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1.
Trials ; 24(1): 413, 2023 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-37337241

RESUMO

BACKGROUND: New treatment strategies are required against infections caused by Helicobacter pylori, which grows increasingly resistant to antibiotics. Polymerase chain reaction-based methods for antibiotic susceptibility testing are available for detecting H. pylori-specific mutations that confer resistance to clarithromycin and levofloxacin. Several meta-analyses have compared eradication rates for susceptibility-guided versus empirical therapy for H. pylori treatment; however, all have significant limitations and high heterogeneity, and the results are contradictory. The main objective of this trial is to assess whether a sequential strategy based on molecular susceptibility testing-guided therapy for H. pylori has a better eradication rate than empirical therapy. METHODS: This trial is designed as a prospective, randomised, open-label, active-controlled and single-centre study. Men and women who are H. pylori-positive, naïve to treatment, and aged 18-65 years will be recruited. A total of 500 participants will be randomised to receive either empirical therapy or a susceptibility-guided sequential strategy. Bismuth quadruple therapy will be the empirical first-line therapy, and in case of failure, high-dose dual (proton-pump inhibitor + amoxicillin) treatment will be the rescue therapy. For the susceptibility-guided sequential strategy, regimen selection will be based on H. pylori susceptibility to clarithromycin (first-line) and levofloxacin (rescue). A first-line treatment of clarithromycin triple therapy will be selected for clarithromycin-sensitive strains. For clarithromycin resistance, a high-dose dual therapy will be selected. During the rescue treatment, a levofloxacin quadruple regimen will be selected for levofloxacin-sensitive strains, and a furazolidone quadruple regimen will be selected for others. The primary outcome is the first-line eradication rate in both groups, and the overall (including first and rescue therapies) H. pylori eradication rate in both groups is one of the secondary outcomes. The eradication rates of H. pylori will be analysed by intention-to-treat analysis, modified intention-to-treat analysis, and per-protocol analysis. DISCUSSION: This randomised controlled trial will provide objective and valid evidence about the value of polymerase chain reaction-based molecular methods for antibiotic susceptibility testing in guiding H. pylori eradication. TRIAL REGISTRATION: Clinicaltrials.gov NCT05549115. Released on 18 September 2022. First posted on 22 September 2022. Enrolment of the first participant on 20 September 2022. The study is retrospectively registered.


Assuntos
Infecções por Helicobacter , Helicobacter pylori , Masculino , Humanos , Feminino , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/tratamento farmacológico , Claritromicina/efeitos adversos , Helicobacter pylori/genética , Levofloxacino/efeitos adversos , Estudos Prospectivos , Quimioterapia Combinada , Antibacterianos/efeitos adversos , Inibidores da Bomba de Prótons/efeitos adversos , Metronidazol , Resultado do Tratamento , Ensaios Clínicos Controlados Aleatórios como Assunto
2.
J Clin Lab Anal ; 37(2): e24825, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36592991

RESUMO

BACKGROUND: As EIF3D is oncogenic in colorectal cancer (CRC) and is associated with multidrug resistance, this study aims to investigate whether and how EIF3D regulates resistance to 5-fluorouracil (5-Fu) in CRC. METHODS: EIF3D-associated genes in CRC were predicted using bioinformatics tools. CRC cells and nude mice received 5-Fu treatment. Then, the impacts of EIF3D and the interaction between EIF3D and RUVBL1 on cell viability, colony formation, apoptosis, and DNA damage were detected through MTT, colony formation, flow cytometry, and immunofluorescence assays, and those on in vivo tumorigenesis through murine xenograft assay. IC50 value of 5-Fu for CRC cells was determined by probit regression analysis. Expressions of EIF3D, eIF4E, EIF3D-associated genes, γH2AX, Bcl-2, Bax, and Cleaved Caspase-3/Caspase-3 in CRC tissues, cells, and/or xenograft tumors were analyzed by qRT-PCR and/or Western blot. RESULTS: EIF3D and RUVBL1 were highly expressed and positively correlated with CRC tissues/cells. In CRC cells, except for eIF4E, both EIF3D and RUVBL1 levels were upregulated by 5-Fu treatment; in addition to that, RUVBL1 level was downregulated by EIF3D silencing rather than eIF4E. Meanwhile, EIF3D silencing diminished IC50 value of 5-Fu and potentiated 5-Fu-induced viability decrease, colony formation inhibition, apoptosis promotion, Bcl-2 downregulation, and γH2AX, Bax, and Cleaved Caspase-3/Caspase-3 upregulation but reversed 5-Fu-triggered RUVBL1 upregulation. RUVBL1 overexpression offsets EIF3D silencing-induced viability decrease and apoptosis promotion of 5-Fu-treated CRC cells, and tumorigenesis suppression and apoptosis promotion in 5-Fu-treated mice. CONCLUSION: EIF3D promotes resistance to 5-Fu in CRC through upregulating RUVBL1 level.


Assuntos
Neoplasias Colorretais , Fluoruracila , Humanos , Animais , Camundongos , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Caspase 3/metabolismo , Camundongos Nus , Proteína X Associada a bcl-2/metabolismo , Fator de Iniciação 4E em Eucariotos , Resistencia a Medicamentos Antineoplásicos/genética , Carcinogênese , Neoplasias Colorretais/genética , Linhagem Celular Tumoral , Apoptose , Proliferação de Células , ATPases Associadas a Diversas Atividades Celulares/metabolismo , ATPases Associadas a Diversas Atividades Celulares/uso terapêutico , Proteínas de Transporte , DNA Helicases/metabolismo
3.
Am J Cancer Res ; 7(9): 1971-1977, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28979818

RESUMO

BACKGROUND: We conducted a phase II study by combining FOLFOX4 plus bevacizumab (BV) with erlotinib (ER) as second-line chemotherapy for patients with metastatic colorectal cancer (mCRC). METHODS: Patients were divided into two groups in randomized double-blind manner. One group was given FOLFOX4 plus 5 mg/kg BV on day 1 of 2-week cycle. The other group was given 2-week-cycle of BV + FOLFOX4, and 100 mg ER every day. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), clinical response rates and adverse events (AEs). RESULTS: 66 patients received 2nd-line treatment of ER + BV+ FOLFOX4, and 65 received BV + FOLFOX4. Median PFS was 9.6 months of ER + BV + FOLFOX4 group, significantly better than 6.9 months of BV + FOLFOX4 group (P = 0.021, HR = 1.15, 95% CI = 0.88-1.39). Medium OS for ER + BV + FOLFOX4 group was 12.5 months, not statistically different than 12.1 months for BV + FOLFOX4 group (P = 00.146, HR = 0.63, 95% CI = 0.34-1.02). Combined partial response and stable disease rate was 48.5% for ER + BV + FOLFOX4 group, significantly higher than 32.2% for BV + FOLFOX4 group (P = 0.015). Patients in ER + BV + FOLFOX4 group had higher incidence rates of AEs. CONCLUSION: In second-line chemotherapy for patients with mCRC, combining erlotinib with FOLFOX4 plus bevacizumab may improve PFS, clinical response rates, but not OS. AEs, though with high incidence rates, were generally tolerable among patients receiving multiple reagents.

4.
World J Surg Oncol ; 13: 307, 2015 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-26499380

RESUMO

BACKGROUND: Klotho is a discovered aging suppressor gene, and its overexpression in mice extends the life span of the animal. Recently, Klotho is also identified as a tumor suppressor gene in variety of tumors; however, the potential role and the antitumor mechanism remain unclarified in liver cancers. METHODS: RT-PCR and western blotting analysis were used to detect the expression of Klotho, ß-catenin, C-myc, and Cyclin D1. MTT assay was used to detect the survival rates of HepG2 and SMMC-7721 cells. Colony formation assay was used to test the proliferation ability in Klotho transfected cells. FACS was used to detect the cell apoptosis rate in different groups. RESULTS: The results showed that lower expression of Klotho were found in liver cancer cell lines than the immortalized liver cell L02. Also, MTT assay results found that overexpression or recombinant Klotho administration suppressed the proliferation of liver cancer cells HepG2 and SMMC-7721. Moreover, the colony formation assay results showed that the number of colonies was significantly lower in the cells with transfection with pCMV-Klotho than the controls. Thus, functional analysis demonstrated that Klotho expression inhibited the proliferation of liver cancer cells and Klotho worked as an important antitumor gene in tumor progression. Next, the mechanism was partly clarified that Klotho expression induced cell apoptosis in HepG2 and SMMC-7721 cells, and this phenomenon was mainly involved in the Wnt/ß-catenin signaling pathway. The western blotting analysis revealed that overexpression or recombinant administration of Klotho obviously decreased the expression levels of ß-catenin, C-myc, and Cyclin D1 in HepG2 cells. Most importantly, the antitumor mechanism for Klotho due to that overexpression of Klotho not only decreased the endogenous ß-catenin levels but also inhibited the nuclear translocation of ß-catenin to delay the cell cycle progression. CONCLUSIONS: Klotho was a tumor suppressor gene, and overexpression of Klotho suppressed the proliferation of liver cancer cells partly due to negative regulation of Wnt/ß-catenin signaling pathway. So, Klotho might be used as a potential target, and the study will contribute to treatment for therapy of liver cancer patients.


Assuntos
Apoptose , Carcinoma Hepatocelular/patologia , Glucuronidase/metabolismo , Neoplasias Hepáticas/patologia , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Western Blotting , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proliferação de Células , Ensaio de Unidades Formadoras de Colônias , Citometria de Fluxo , Glucuronidase/genética , Humanos , Proteínas Klotho , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Camundongos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Proteínas Wnt/genética , beta Catenina/genética
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